Antiviral Activity of Bictegravir and Cabotegravir Against Integrase Inhibitor Resistant SIVmac239 and HIV-1 [PublishAheadOfPrint]

Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase (IN) strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance while a fourth compound termed cabotegravir (CAB) is currently in late phases of clinical development.

Here we report the susceptibilities of simian immunodeficiency virus (SIV) and HIV-1 IN mutants containing various RAMs to BIC, CAB, and DTG. BIC potently inhibited SIV and HIV-1 in single cycle infection with EC₅₀s in the low nM range. In single cycle SIV infections, none of the E92Q, T97A, Y143R or N155H substitutions had a significant effect on susceptibility to BIC (≤4-fold increase in EC₅₀) whereas G118R and R263K conferred ~14-fold and ~ 6-fold increases in EC₅₀, respectively. In both single and multiple round of HIV-1 infections, BIC remained active against the Y143R, N155H, R263K, R263K/M50I, and R263K/E138K mutants (≤4-fold increase in EC₅₀). In multiple round of infections, the G140S/Q148H combination of substitutions decreased HIV-1 susceptibility to BIC 4.8-fold compared to 16.8- and 7.4-fold for CAB and DTG, respectively. BIC possesses an excellent resistance profile in regard to HIV and SIV and could be useful in non-human primate models of HIV infection.

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